Prostatic Neoplasms: Walsh PC

Mohler J, Babaian RJ, Bahnson RR, Boston B, D'Amico A, Eastham JA, Hauke RJ, Huben RP, Kantoff P, Kawachi M, Kuettel M, Lange PH, Logothetis C, MacVicar G, Pollack A, Pow-Sang JM, Roach M, Sandler H, Shrieve D, Srinivas S, Twardowski P, Urban DA, Walsh PC, Anonymous00332. · No affiliation provided · J Natl Compr Canc Netw. · Pubmed #17692170 No free full text.

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Walsh PC. · No affiliation provided · J Urol. · Pubmed #15879791 No free full text.

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Bahnson RR, Hanks GE, Huben RP, Kantoff P, Kozlowski JM, Kuettel M, Lange PH, Logothetis C, Pow-Sang JM, Roach M, Sandler H, Scardino PT, Taylor RJ, Urban DA, Walsh PC, Wilson TG, Anonymous00207. · James Cancer Hospital and Solove Research Institute at Ohio State University, Columbus, Ohio, USA. · Oncology (Williston Park). · Pubmed #11195405 No free full text.

Abstract: Systemic therapies for prostate cancer are likely to improve, and as they do, they will have enormous impact on the treatment of high-risk and locally advanced cancers. Further technical improvements in radiotherapy and alternative local modalities, such as cryoablation, are also likely, and will bring even more options for local control. It is certain these guidelines will continue to evolve.

Walsh PC. · No affiliation provided · N Engl J Med. · Pubmed #12226156 No free full text.

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Walsh PC. · No affiliation provided · Urology. · Pubmed #11377297 No free full text.

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Eisenberger MA, Walsh PC. · No affiliation provided · N Engl J Med. · Pubmed #10588970 No free full text.

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Walsh PC, DeWeese TL, Eisenberger MA. · James Buchanan Brady Urological Institute, the Sidney Kimmel Comprehensive Cancer Center, the Department of Urology, Radiation Oncology and Molecular Radiation Sciences, and Johns Hopkins Medical Institutions, Baltimore, MD 21287-2101, USA. · N Engl J Med. · Pubmed #18160689 No free full text.

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Cannon GM, Walsh PC, Partin AW, Pound CR. · Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania 15232, USA. · Urology. · Pubmed #14747037 No free full text.

Abstract: After primary treatment for clinically localized prostate cancer, biochemical recurrence is usually the first evidence of either local recurrence or metastatic progression. This poses a diagnostic dilemma for both the patient and the physician regarding future therapy. Prostate-specific antigen doubling time (PSADT) is a useful tool in this clinical setting. There have been multiple reports of the utility of PSADT in men with isolated biochemical recurrence after either radical prostatectomy or external-beam radiation therapy. Early observations of PSADT in men with recurrence are reviewed and the current literature is summarized to allow physicians to make an accurate assessment of a patient's risk of progression after isolated biochemical recurrence.

Han M, Partin AW, Pound CR, Epstein JI, Walsh PC. · James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. · Urol Clin North Am. · Pubmed #11590814 No free full text.

Abstract: In a large series of 2404 men with a mean follow-up of 6.3 plus or minus 4.2 years (range, 1-17) after anatomic RRP for clinically localized prostate cancer, 412 men (17%) have recurred. A detectable PSA was the only evidence of recurrence in 9.7%, whereas 1.7% and 5.8% had local recurrence and distant metastasis, respectively. The overall actuarial 5-, 10-, and 15-year recurrence-free survival rates for these men were 84%, 74%, and 66%, respectively. As demonstrated in the authors' previous reports, the actuarial likelihood of a postoperative recurrence increased with advancing clinical stage, Gleason-score, preoperative PSA level, and pathologic stage. Subdivision of men with Gleason 7 tumors resulted in better stratification. There was a similar actuarial likelihood of postoperative recurrence for men with Gleason 4 + 3 and Gleason score 8 to 10 disease. The actuarial rate of recurrence of tumor for men with Gleason 3 + 4 disease was statistically different from the rate for men with Gleason score 6 or Gleason 4 + 3 disease. The overall actuarial metastasis-free survival rates at 5, 10, and 15 years were 96%, 90%, and 82%, respectively. The overall actuarial cancer-specific survival rates at 5, 10, and 15 years were 99%, 96%, and 90%, respectively. This study provides long-term outcome of patients with clinically localized cancer who underwent RRP between 1982 and 1999. Recognizing that this long-term study includes many patients with more advanced disease diagnosed before the PSA era, caution must be exercised in comparing these results with the outcomes for cohorts of patients treated since 1989. Anatomic RRP is an effective way to manage clinically localized prostate cancer. Excellent long-term results can be obtained with RRP for early stage disease. The proportion of men with early stage prostate cancer will continue to increase with wide use of serum PSA testing and digital rectal examination.

Loeb S, Schaeffer EM, Chan DW, Carter HB, Walsh PC, Sokoll LJ. · Department of Pathology, Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA. · Urology. · Pubmed #19394489 No free full text.

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Walsh PC. · No affiliation provided · J Urol. · Pubmed #16093992 No free full text.

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Walsh PC. · No affiliation provided · J Urol. · Pubmed #15879792 No free full text.

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Parsons JK, Marschke P, Maples P, Walsh PC. · James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA. · Urology. · Pubmed #15533491 No free full text.

Abstract: OBJECTIVES: To determine whether postoperative methylprednisolone improves the recovery of sexual function after nerve-sparing radical retropubic prostatectomy. METHODS: We randomized men undergoing bilateral nerve-sparing radical retropubic prostatectomy by a single surgeon to receive 6 days of placebo or methylprednisolone beginning on postoperative day 1. At 3, 6, and 12 months postoperatively, we assessed potency with the abbreviated International Index of Erectile Function questionnaire and urinary continence with participant-reported pad use. We used the chi-square test, Fisher's exact test, and the two-sample t test with equal variances for comparisons between study groups. RESULTS: No operative complications occurred and 70 (100%) of 70 participants experienced normal wound healing. The odds of being potent for participants who received methylprednisolone (n = 34) compared with those who received placebo (n = 36) did not significantly differ at 3 (odds ratio 0.29, 95% confidence interval 0.08 to 1.05), 6 (odds ratio 0.63, 95% confidence interval 0.17 to 2.4), or 12 (odds ratio 1.18, 95% confidence interval 0.29 to 4.8) months. The mean International Index of Erectile Function scores did not significantly differ at 3 (P = 0.08), 6 (P = 0.50), or 12 (P = 0.71) months. At 12 months, 74% of the methylprednisolone and 71% of the placebo participants were potent (P = 0.8). The proportions of participants who were continent did not differ significantly at 3 (P = 0.89), 6 (P = 0.25), or 12 (P = 0.49) months. At 12 months, 96% of the methylprednisolone and 100% of the placebo participants were continent. CONCLUSIONS: At doses sufficient to produce a systemic anti-inflammatory effect, postoperative methylprednisolone was not associated with improved potency at up to 12 months after bilateral nerve-sparing radical retropubic prostatectomy in men 40 to 60 years old.

Freedland SJ, Partin AW, Epstein JI, Walsh PC. · Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA. · Cancer. · Pubmed #15073852 links to  free full text

Abstract: BACKGROUND: The 1997 TNM staging system for prostate carcinoma defines a pT2a disease as a tumor histologically involving one lobe of the prostate and pT2b disease as a tumor histologically involving both prostatic lobes. Whether this distinction provides prognostic significance is unclear. The authors evaluated biochemical outcomes between men with pT2aN0 and pT2bN0 disease. METHODS: The authors identified 1606 men with organ-confined disease (pT2N0) who were treated with radical prostatectomy between 1982 and 2003 by one surgeon. Clinical characteristics were compared between men with pT2a and pT2b tumors using rank-sum analysis, and prostate-specific antigen (PSA) recurrence data were compared using log-rank analysis. The significant independent predictors of PSA recurrence were determined using a multivariate Cox proportional hazards model. RESULTS: There were no significant differences between men with pT2a and pT2b tumors at the time of surgery in terms of clinicopathologic characteristics (biopsy and pathologic Gleason score, serum PSA level, clinical stage, and age). Log-rank analysis revealed no significant differences in time to PSA recurrence between men with pT2a and pT2b tumors (P = 0.755). The 10-year PSA progression-free survival rate was 95% (confidence interval [CI], 92-97%) for men with pT2a tumors and 93% (CI, 90-95%) for men with pT2b tumors. Multivariate analysis showed that the significant predictors of PSA recurrence included serum PSA level, biopsy and pathologic Gleason score, and clinical stage. In the current cohort of men with organ-confined disease, pathologic stage (pT2a vs. pT2b) was not a significant predictor of PSA recurrence on multivariate analysis. CONCLUSIONS: There was no difference in PSA recurrence rates between men with pT2aN0 versus pT2bN0 tumors. In men with organ-confined disease, radical prostatectomy provided excellent 10-year PSA progression-free survival regardless of tumor burden (pT2a vs. pT2b). Consideration should be given to modifying the TNM staging system to eliminate substratification of pT2 tumors.

Feneley MR, Landis P, Simon I, Metter EJ, Morrell CH, Carter HB, Walsh PC. · James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. · Urology. · Pubmed #11068313 No free full text.

Abstract: OBJECTIVES: To examine the relationship between prostate size and the method of cancer detection in men with organ-confined prostate cancer, and compare prostate size in men with and without cancer. METHODS: Prostate volume was evaluated in 720 men who had undergone radical prostatectomy for Stage T1c or Stage T2 cancer. Men with Stage T2 cancer were divided into those treated before 1989 (when widespread prostate-specific antigen [PSA] testing began), or not. Gland volume was also examined in 265 men participating in the Baltimore Longitudinal Study of Aging who had no clinical evidence of cancer. Volumes were compared using linear regression to allow for age. RESULTS: Prostate volume in men with Stage T1c cancer was statistically significantly larger than in men with Stage T2 cancer diagnosed in the pre-PSA era after adjusting for age (P = 0.0001), and statistically significantly larger than in men without cancer above age 47 years based on 95% confidence intervals. Prostate volumes in men with Stage T2 cancer diagnosed in the pre-PSA era and in men without cancer were not statistically significantly different. CONCLUSIONS: Prostate volume in men with PSA-detected, organ-confined cancer is larger than in men with palpable organ-confined cancer diagnosed in either the pre-PSA era or PSA era. These discrepancies may reflect a diagnostic bias due to the effect of benign prostatic hyperplasia on serum PSA that results in the selection of men with larger prostates for biopsy.

Chan TY, Partin AW, Walsh PC, Epstein JI. · Department of Urology, Johns Hopkins University School of Medicine, James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, Maryland, USA. · Urology. · Pubmed #11068310 No free full text.

Abstract: OBJECTIVES: To determine the clinical significance of Gleason score 3+4 versus 4+3 on radical prostatectomy. METHODS: Of 2390 men who underwent radical prostatectomy by a single surgeon, 570 had Gleason score 7 tumors without lymph node metastasis, seminal vesicle invasion, or tertiary Gleason pattern 5. Patients were evaluated for biochemical recurrence (prostate-specific antigen progression) and distant metastases. RESULTS: Eighty percent of patients had Gleason score 3+4, 20% had 4+3. The rate of established extraprostatic extension at radical prostatectomy for Gleason score 3+4 and 4+3 tumors was 38.2% and 52.7%, respectively (P = 0.008). With a mean follow-up of 4.6 years for men without progression, Gleason score 4+3 tumors had an increased risk of progression independent of stage and margin status (P <0.0001). The 5-year actuarial risk of progression was 15% and 40% for Gleason score 3+4 and 4+3 tumors, respectively. The mean time to progression was 4.4 years for Gleason score 3+4 tumors and 3.2 years for Gleason score 4+3 tumors. We stratified the patients into four prognostic groups on the basis of organ-confined status, margin status, and Gleason score (3+4 versus 4+3). The 5-year actuarial risk of progression was 10%, 35%, 45%, and 61%, with 10-year progression rates of 29%, 42%, 69%, and 84%, for the four groups. 3.9% of patients with Gleason score 3+4 and 10. 5% with Gleason score 4+3 tumors developed metastatic disease within a mean of 5.7 and 5.6 years, respectively. A Gleason score of 4+3 versus 3+4 was predictive of metastatic disease (P = 0.002) but not local recurrence. CONCLUSIONS: Gleason score 7 tumors are heterogeneous in their biologic behavior. The differences in prognosis for patients with Gleason scores 3+4 and 4+3 tumors at radical prostatectomy are significant. Although the assessment of the percentage of pattern 4 at radical prostatectomy is not likely to be reproducible, the distinction between Gleason score 3+4 and 4+3 should be easier for pathologists to perform.

Catalona WJ, Southwick PC, Slawin KM, Partin AW, Brawer MK, Flanigan RC, Patel A, Richie JP, Walsh PC, Scardino PT, Lange PH, Gasior GH, Loveland KG, Bray KR. · Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA. · Urology. · Pubmed #10925089 No free full text.

Abstract: OBJECTIVES: Various methods have been proposed to increase the specificity of prostate-specific antigen (PSA), including age-specific PSA reference ranges, PSA density (PSAD), and percent free PSA (%fPSA). In this multicenter study, we compared these methods for their utility in cancer detection and their ability to predict pathologic stage after radical prostatectomy in patients with clinically localized, Stage T1c cancer. METHODS: Seven hundred seventy-three men (379 with prostate cancer, 394 with benign prostatic disease), 50 to 75 years old, from seven medical centers were enrolled in this prospective blinded study. All subjects had a palpably benign prostate, PSA 4.0 to 10.0 ng/mL, and a histologically confirmed diagnosis. Hybritech's Tandem PSA and free PSA assays were used. RESULTS: %fPSA and age-specific PSA cutoffs enhanced PSA specificity for cancer detection, but %fPSA maintained significantly higher sensitivities. Age-specific PSA cutoffs missed 20% to 60% of cancers in men older than 60 years of age. %fPSA and PSAD performed equally well for detection (95% sensitivity) if cutoffs of 25% fPSA or 0.078 PSAD were used. The commonly used PSAD cutoff of 0.15 detected only 59% of cancers. %fPSA and PSAD also produced similar results for prediction of the post-radical prostatectomy pathologic stage. Patients with cancer with higher %fPSA values (greater than 15%) or lower PSAD values (0.15 or less) tended to have less aggressive disease. CONCLUSIONS: The results of this study demonstrated that cancer detection (sensitivity) is significantly higher with %fPSA than with age-specific PSA reference ranges. %fPSA and PSAD provide comparable results, suggesting that %fPSA may be used in place of PSAD for biopsy decisions and in algorithms for prediction of less aggressive tumors since the determination of %fPSA does not require ultrasound.

Catalona WJ, Partin AW, Slawin KM, Naughton CK, Brawer MK, Flanigan RC, Richie JP, Patel A, Walsh PC, Scardino PT, Lange PH, deKernion JB, Southwick PC, Loveland KG, Parson RE, Gasior GH. · Division of Urologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA. · Urology. · Pubmed #10699613 No free full text.

Abstract: OBJECTIVES: In predominately white populations, measurement of the percentage of free prostate-specific antigen (%fPSA) has been shown to enhance the specificity of total PSA testing for prostate cancer while maintaining high sensitivity and to aid in prostate cancer staging. This study evaluated whether the %fPSA cutoff that maintained a 95% sensitivity in a white population yielded the same sensitivity and specificity in a black population and whether %fPSA was useful in predicting postoperative pathologic features in blacks. METHODS: We evaluated 647 white and 79 black men, prospectively enrolled at prostate cancer screening and surgical referral centers. Subjects were 50 to 75 years old with digital rectal examination findings that were not suspicious for prostate cancer and total PSA values between 4.0 and 10.0 ng/mL. All had undergone needle biopsy of the prostate. Hybritech's Tandem total and free PSA assays were used. RESULTS: Ninety-five percent sensitivity was attained with a %fPSA cutoff of 25% in both races. Use of this cutoff could have avoided unnecessary biopsies in 20% of white and 17% of black subjects (P = 0.69). In receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) for %fPSA was significantly higher than for total PSA in both blacks (0.76 versus 0.56, P <0.01) and whites (0.70 versus 0.54, P <0.001). In both races, higher %fPSA values indicated a lower risk of cancer and also predicted favorable pathologic features in radical prostatectomy specimens. CONCLUSIONS: A 25% fPSA cutoff detected 95% of cancers and reduced unnecessary biopsies in both races. Higher %fPSA values were associated with favorable postoperative histopathologic findings in both races.

Southwick PC, Catalona WJ, Partin AW, Slawin KM, Brawer MK, Flanigan RC, Patel A, Richie JP, Walsh PC, Scardino PT, Lange PH, Gasior GH, Parson RE, Loveland KG. · Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA. · J Urol. · Pubmed #10492194 No free full text.

Abstract: PURPOSE: Prostate specific antigen (PSA) exists in bound (complexed) and unbound (free) forms in serum. The percentage of free PSA enhances the specificity of PSA testing for prostate cancer detection. We evaluated the use of percent free PSA preoperatively to predict pathological stage. MATERIALS AND METHODS: A total of 379 men with prostate cancer and 394 with benign prostatic disease 50 to 75 years old were enrolled in this prospective study at 7 medical centers. All subjects had a palpably benign prostate gland, serum PSA 4.0 to 10.0 ng./ml. and a histologically confirmed diagnosis. The Hybritech Tandem PSA and free PSA assays were used. Of the 379 cancer patients 268 (71%) underwent radical prostatectomy. RESULTS: Higher percent free PSA levels were associated with more favorable histopathological findings in prostatectomy specimens. A value of 15% free PSA provided the greatest discrimination in predicting favorable pathological outcome. Organ confined cancer, Gleason sum less than 7 and small tumors (10% or less involvement of the prostate) were noted in 75% of patients with greater than 15% and only 34% with 15% or less free PSA (p<0.001). Multivariate logistic regression analysis revealed percent free PSA to be the strongest predictor of postoperative pathological outcome (odds ratio 2.25), followed by biopsy Gleason sum (2.06) and patient age (1.35). Total PSA was not predictive in this cohort but has been shown in prior studies to be predictive of outcome when a broader range of PSA values is evaluated. CONCLUSIONS: Percent free PSA may be used for risk assessment of the presence (diagnosis) and stage of prostate cancer in men with PSA between 4 and 10 ng./ml. Percent free PSA may be combined with PSA, digital rectal examination and biopsy findings to help predict postoperative pathological stage and grade, and may assist the patient and physician in making more informed treatment decisions.

Kader AK, Sun J, Isaacs SD, Wiley KE, Yan G, Kim ST, Fedor H, DeMarzo AM, Epstein JI, Walsh PC, Partin AW, Trock B, Zheng SL, Xu J, Isaacs W. · Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA. · Prostate. · Pubmed #19434657 No free full text.

Abstract: BACKGROUND: More than a dozen single nucleotide polymorphisms (SNPs) have been associated with prostate cancer (PCa) risk from genome-wide association studies (GWAS). Their association with PCa aggressiveness and clinicopathologic variables is inconclusive. METHODS: Twenty PCa risk SNPs implicated in GWAS and fine mapping studies were evaluated in 5,895 PCa cases treated by radical prostatectomy at Johns Hopkins Hospital, where each tumor was uniformly graded and staged using the same protocol. RESULTS: For 18 of the 20 SNPs examined, no statistically significant differences (P > 0.05) were observed in risk allele frequencies between patients with more aggressive (Gleason scores > or =4 + 3, or stage > or =T3b, or N+) or less aggressive disease (Gleason scores < or =3 + 4, and stage < or =T2, and N0). For the two SNPs that had significant differences between more and less aggressive disease rs2735839 in KLK3 (P = 8.4 x 10(-7)) and rs10993994 in MSMB (P = 0.046), the alleles that are associated with increased risk for PCa were more frequent in patients with less aggressive disease. Since these SNPs are known to be associated with PSA levels in men without PCa diagnoses, these latter associations may reflect the enrichment of low grade, low stage cases diagnosed by contemporary disease screening with PSA. CONCLUSIONS: The vast majority of PCa risk-associated SNPs are not associated with aggressiveness and clinicopathologic variables of PCa. Correspondingly, they have minimal utility in predicting the risk for developing more or less aggressive forms of PCa.

Hsu FC, Sun J, Wiklund F, Isaacs SD, Wiley KE, Purcell LD, Gao Z, Stattin P, Zhu Y, Kim ST, Zhang Z, Liu W, Chang BL, Walsh PC, Duggan D, Carpten JD, Isaacs WB, Grönberg H, Xu J, Zheng SL. · Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA. · Cancer Res. · Pubmed #19318570 No free full text.

Abstract: A two-stage genome-wide association study (GWAS) of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative identified single nucleotide polymorphisms (SNP) in 150 regions across the genome that may be associated with prostate cancer (PCa) risk. We filtered these results to identify 43 independent SNPs where the frequency of the risk allele was consistently higher in cases than in controls in each of the five CGEMS study populations. Genotype information for 22 of these 43 SNPs was obtained either directly by genotyping or indirectly by imputation in our PCa GWAS of 500 cases and 500 controls selected from a population-based case-control study in Sweden [Cancer of the Prostate in Sweden (CAPS)]. Two of these 22 SNPs were significantly associated with PCa risk (P<0.05). We then genotyped these two SNPs in the remaining cases (n=2,393) and controls (n=1,222) from CAPS and found that rs887391 at 19q13 was highly associated with PCa risk (P=9.4 x 10(-4)). A similar trend of association was found for this SNP in a case-control study from Johns Hopkins Hospital (JHH), albeit the result was not statistically significant. Altogether, the frequency of the risk allele of rs887391 was consistently higher in cases than controls among each of seven study populations examined, with an overall P=3.2 x 10(-7) from a combined allelic test. A fine-mapping study in a 110-kb region at 19q13 among CAPS and JHH study populations revealed that rs887391 was the most strongly associated SNP in the region. Additional confirmation studies of this region are warranted.

Xu J, Isaacs SD, Sun J, Li G, Wiley KE, Zhu Y, Hsu FC, Wiklund F, Turner AR, Adams TS, Liu W, Trock BJ, Partin AW, Chang B, Walsh PC, Grönberg H, Isaacs W, Zheng S. · Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA. · Clin Cancer Res. · Pubmed #18794092 No free full text.

Abstract: PURPOSE: Fifteen independent genetic variants have been implicated in prostate cancer risk by recent genome-wide association studies. However, their association with clinicopathologic features of prostate cancer is uncertain. EXPERIMENTAL DESIGN: We systematically evaluated these 15 variants in 1,563 prostate cancer patients undergoing radical prostatectomy, taking advantage of the uniform tumor stage and grade information available for each of these cases. Associations of these variants with aggressiveness, pathologic Gleason scores, pathologic stage, age at diagnosis, or serum prostate-specific antigen (PSA) levels were tested. RESULTS: After adjusting for multiple testing, none of the single nucleotide polymorphisms was individually or cumulatively associated with aggressiveness or individual clinicopathologic variables of prostate cancer such as Gleason scores, pathologic stage, or age at diagnosis of prostate cancer. The reported risk allele (G) for single nucleotide polymorphism rs2735839 in the KLK3 gene at 19q13 was more frequent in less aggressive prostate cancer patients (0.89) than in more aggressive prostate cancer patients (0.86; nominal P = 0.03) or in controls (0.86; nominal P = 0.04). Considering that this allele was also significantly associated with higher serum PSA levels among controls (nominal P = 0.003), the observed trend of higher frequency of this risk allele between less and more aggressive prostate cancer, or between less aggressive and controls may be due to detection bias of PSA screening. CONCLUSIONS: Prostate cancer risk variants recently discovered from genome-wide case-control association studies are not associated with clinicopathologic variables in this population. Case-case studies are urgently needed to discover genetic variants that predict tumor aggressiveness.

Sun J, Zheng SL, Wiklund F, Isaacs SD, Purcell LD, Gao Z, Hsu FC, Kim ST, Liu W, Zhu Y, Stattin P, Adami HO, Wiley KE, Dimitrov L, Sun J, Li T, Turner AR, Adams TS, Adolfsson J, Johansson JE, Lowey J, Trock BJ, Partin AW, Walsh PC, Trent JM, Duggan D, Carpten J, Chang BL, Grönberg H, Isaacs WB, Xu J. · Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. · Nat Genet. · Pubmed #18758462 No free full text.

Abstract: We carried out a fine-mapping study in the HNF1B gene at 17q12 in two study populations and identified a second locus associated with prostate cancer risk, approximately 26 kb centromeric to the first known locus (rs4430796); these loci are separated by a recombination hot spot. We confirmed the association with a SNP in the second locus (rs11649743) in five additional populations, with P = 1.7 x 10(-9) for an allelic test of the seven studies combined. The association at each SNP remained significant after adjustment for the other SNP.

Trock BJ, Han M, Freedland SJ, Humphreys EB, DeWeese TL, Partin AW, Walsh PC. · Brady Urological Institute, Johns Hopkins School of Medicine, 600 N Wolfe St, 546 Phipps Bldg, Baltimore, MD 21287, USA. · JAMA. · Pubmed #18560003 links to  free full text

Abstract: CONTEXT: Biochemical disease recurrence after radical prostatectomy often prompts salvage radiotherapy, but no studies to date have had sufficient numbers of patients or follow-up to determine whether radiotherapy improves survival, and if so, the subgroup of men most likely to benefit. OBJECTIVES: To quantify the relative improvement in prostate cancer-specific survival of salvage radiotherapy vs no therapy after biochemical recurrence following prostatectomy, and to identify subgroups for whom salvage treatment is most beneficial. DESIGN, SETTING, AND PATIENTS: Retrospective analysis of a cohort of 635 US men undergoing prostatectomy from 1982-2004, followed up through December 28, 2007, who experienced biochemical and/or local recurrence and received no salvage treatment (n = 397), salvage radiotherapy alone (n = 160), or salvage radiotherapy combined with hormonal therapy (n = 78). MAIN OUTCOME MEASURE: Prostate cancer-specific survival defined from time of recurrence until death from disease. RESULTS: With a median follow-up of 6 years after recurrence and 9 years after prostatectomy, 116 men (18%) died from prostate cancer, including 89 (22%) who received no salvage treatment, 18 (11%) who received salvage radiotherapy alone, and 9 (12%) who received salvage radiotherapy and hormonal therapy. Salvage radiotherapy alone was associated with a significant 3-fold increase in prostate cancer-specific survival relative to those who received no salvage treatment (hazard ratio [HR], 0.32 [95% confidence interval {CI}, 0.19-0.54]; P<.001). Addition of hormonal therapy to salvage radiotherapy was not associated with any additional increase in prostate cancer-specific survival (HR, 0.34 [95% CI, 0.17-0.69]; P = .003). The increase in prostate cancer-specific survival associated with salvage radiotherapy was limited to men with a prostate-specific antigen doubling time of less than 6 months and remained after adjustment for pathological stage and other established prognostic factors. Salvage radiotherapy initiated more than 2 years after recurrence provided no significant increase in prostate cancer-specific survival. Men whose prostate-specific antigen level never became undetectable after salvage radiotherapy did not experience a significant increase in prostate cancer-specific survival. Salvage radiotherapy also was associated with a significant increase in overall survival. CONCLUSIONS: Salvage radiotherapy administered within 2 years of biochemical recurrence was associated with a significant increase in prostate cancer-specific survival among men with a prostate-specific antigen doubling time of less than 6 months, independent of other prognostic features such as pathological stage or Gleason score. These preliminary findings should be validated in other settings, and ultimately, in a randomized controlled trial.

Sun J, Chang BL, Isaacs SD, Wiley KE, Wiklund F, Stattin P, Duggan D, Carpten JD, Trock BJ, Partin AW, Walsh PC, Grönberg H, Xu J, Isaacs WB, Zheng SL. · Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. · Prostate. · Pubmed #18491292 No free full text.

Abstract: BACKGROUND: A strong cumulative effect of five genetic variants and family history on prostate cancer risk was recently reported in a Swedish population (CAPS). We carried out this study to confirm the finding in two U.S. study populations and perform a combined analysis to obtain a more stable estimate of the odds ratio (OR) for prostate cancer. METHODS: We evaluated three SNPs at 8q24 and one SNP each at 17q12 and 17q24.3 in two study populations in the U.S. The first was a hospital-based case-control study population at Johns Hopkins Hospital (JHH), including 1,563 prostate cancer patients and 576 control subjects. The second was the National Cancer Institute Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, including 1,172 prostate cancer patients and 1,157 control subjects. RESULTS: We confirmed a cumulative effect of five risk variants on prostate cancer risk. Based on a total of 5,628 cases and 3,514 controls from JHH, CGEMS, and CAPS, men who carry any combination of 1, 2, 3, and 4 or more of these five risk variants have an estimated OR (95% CI) of 1.41 (1.20-1.67), 1.88 (1.59-2.22), 2.36 (1.95-2.85), and 3.80 (2.77-5.22) for prostate cancer, respectively, compared to men who do not have any of these five risk variants. When family history was included, the cumulative effect was stronger. DISCUSSION: These results provide an important confirmation for the cumulative effect of five genetic risk variants on prostate cancer risk. The more stable OR estimates of the cumulative effect of these six risk factors are a major step toward individual risk characterization for this disease.